The objectives of this proposal are to investigate the molecular and cellular origins of pancreatic ductal adenocarcinoma (PDA) through the use of genetically defined mouse models. The principal investigator, Dr. Sunil R. Hingorani, is a physician-scientist whose longterm interests are in applying fundamental research discoveries toward the improved care of pancreatic cancer patients. Now the fourth leading cause of cancer-related deaths in this country, PDA is a disease with a rising incidence and unabated mortality. The underlying premise of the efforts described here holds that a comprehensive understanding of the pathogenesis of this disease requires the generation of animal models that faithfully recapitulate the entire progression scheme beginning with the earliest preinvasive state. Indeed, given the penchant for this disease to metastasize very early in its course, the ability to intervene meaningfully likely requires identification and treatment from its very inception. By targeting endogenous Kras(G12D) expression to progenitor cells of the developing mouse pancreas, a strain of mice has been generated that accurately models all three stages of pancreatic intraepithelial neoplasias (PanlNs), the presumptive precursors to invasive pancreatic cancer. These lesions spontaneously progress to invasive and metastatic ductal adenocarcinoma, demonstrating unequivocally that PanlNs are indeed precursors to PDA. Thus, the first aim is to study the molecular mechanisms by which endogenous Kras(G12D) expression induces the formation of PanIN lesions. Second, the mechanisms by which oncogenic Kras cooperates with a specific point-mutation of the p53 tumor suppressor gene to hasten the development of pancreatic cancer will be investigated. Finally, the cell-of-origin for PDA will be identified by targeting conditional Kras(G12D) expression to discrete cellular compartments of the pancreas. It can be reasonably hoped that the insights gleaned from these endeavors will aid efforts to develop effective early detection methods, identify and test chemopreventive strategies for high-risk patients, and devise potential therapies for early and even advanced stage disease. The NCI Pancreatic Cancer Progress Review Group Report identified the development of gene-based animal models of the disease as a research priority. The research described in this application specifically addresses this priority and is 100% relevant to pancreatic cancer.